Cervical cancer is one of the most common cancers in women and the second leading cause of death by cancer among women. Nearly half of all women who develop this cancer will die from it. Virtually all cervical cancers are caused by sexually transmitted, high-risk human papillomaviruses (HPVs), the most common of which is HPV16. In these cancers, two viral oncogenes are always expressed, E6 and E7 and are believed to be essential for these cancers to arise and persist. Understanding the mechanisms of action of E6 and E7 therefore could provide new insights into how to more effectively treat cervical cancer patients. We have developed HPV transgenic mouse strains in which to study how HPV16 E6 and E7 contribute to cervical cancer. By comparing the cancer incidence in mice expressing wild type or mutant forms of E6 and E7, and by crossing these mice to other genetically engineered mutant mouse strains, we can investigate the role of individual activities of E6 and E7, and the role of cellular genes and pathways in cervical cancer. During the past funding period we have learned that E6 and E7 cause cervical cancer through multiple activities, including but not limited to their inactivation of p53 and pRb, respectively. In this competitive renewal application, we will further define the mechanisms of action of E6 and E7 oncogenes in cervical cancer. We will also investigate the importance of the Notch signaling pathway, which has been directly implicated in cervical cancers. PUBLIC HEALTH RELEVANCE: Human papillomaviruses cause virtually all cervical cancers, the second leading cause of death by cancer among women, as well as other anogenital cancers and a subset of head and neck cancers. Approximately half of women who develop cervical cancer, die from it. By understanding how papillomaviruses cause cervical cancer we can define new means by which to treat more effectively cervical cancer patients and thereby improve their health and their life expectancy.